ErbB3 is a member of the epidermal growth factor receptor (EGFR) family of transmembrane receptor tyrosine kinases (RTKs). Upon stimulation by its ligand, heregulin (HRG), ErbB3 heterodimerizes with another member of the ErbB family of RTKs, such as ErbB1 (EGFR), ErbB2 (HER2) or ErbB4. This heterodimerization initiates multiple signaling cascades leading to downstream effects including cell proliferation and survival. Co-expression of HRG and ErbB3 is found in many cancers and has been associated with decreased overall survival rates. Moreover, a growing body of evidence has shown that ErbB3 signaling causes decreased sensitivity (resistance) to both chemotherapeutic and targeted agents.
Seribantumab (previously MM-121 or Ab #6) is an experimental human monoclonal anti-ErbB3 IgG2; see, e.g., U.S. Pat. Nos. 7,846,440; 8,691,771; 8,895,001 and 8,961,966; U.S. Patent Publication Nos. 20110027291, 20140127238, 20140134170, and 20140248280, as well as international Publication Nos. WO/2015/100459, WO/2013/023043, WO/2013/138371, and WO/2012/103341. It is administered by intravenous infusion (e.g., over the course of one hour) and is supplied as a clear liquid solution in sterile, single-use vials containing 10.1 ml of seribantumab at a concentration of 25 mg/ml in an aqueous solution of 20 mM histidine, 150 mM sodium chloride, pH 6.5, to be stored at 2-8° C.
The significance of ErbB4 in cancer biology is poorly understood, especially given that ErbB4 is either up-regulated or down-regulated in different cancer types. Its correlation with clinical outcome is also conflicting, as reports indicate that ErbB4 is correlated with both favorable and poor prognoses. This conflicting role of ErbB4 might be due to its four structurally and functionally different isoforms that are derived from alternative splicing of the single ErbB4 gene. The “JMa” and “JMb” isoforms differ in the extracellular juxtamembrane (JM) domains, and the “CYT1” and “CYT2” isoforms differ in the intracellular cytoplasmic (CYT) domains. Data from both in vitro and in vivo experiments using ErbB4 isoform-specific overexpressing cell lines suggests that JMa is related to cell proliferation and migration, whereas JMb is related to cell growth inhibition and apoptosis. ErbB4 has been reported to be involved in the resistance mechanism of hormonal or RTK-targeted therapy, and was found to be mutated in 5% of NSCLC and 20% of metastatic melanoma, increasing the interest in ErbB4-targeted therapies.
Identifying and validating biomarkers is critical for targeted therapy. A certain number of clinical trials fail due to misidentification of the appropriate patient population. HRG has been identified as the most important biomarker to predict seribantumab efficacy, and seribantumab is effective in the treatment of HRG-driven tumors by inhibiting HRG binding to ErbB3, and thus inhibiting HRG-induced ErbB3 dimerization with other ErbB proteins. Data from ongoing phase II clinical trials also indicate that seribantumab is effective only in certain patient populations that express HRG (see, e.g., co-pending international Publication No. WO/2015/100459).